Over1.5millionpeopleintheUShabituallyusecocaineeachyear(SAMHSA2013),resultinginmany prematuredeaths,withnotreatmentsavailable.Thegoalofthisproposalistocomparemalesandfemalesand menstrualcyclephaseaswellaswithchallengingimpulsiveandcompulsivedrugtakingschedulesusing3 noveltreatments:1)anondrugreward,asaccharin-sweetenedliquid(SACC).Healthiernondrugrewards, suchasphysicalexercise,havebeenusedtoreducedrugseekinginrats(seeCarroll&Lynch2015)and humans(Rawsonetal.2015),butduetologisticsandsafetyissues,thisisdifficulttoadministerinexisting monkeylabs.However,SACCandexerciseproducesimilarreductionsindrug-seekingbehaviorinrats,and SACCreducesdrug-seekingtoasimilarextentinratsandmonkeys.2)Progesterone(PRO),ahormone involvedinthemenstrualcycleandpregnancy,reducedsubjectiveeffectsofdrugsinhumans(e.g.,Saladinet al.2015)anddrug-seekinginratsandmonkeys(seereviewbyCarroll&Smethells2015).3)Cocaine- hydrolase?CocHisagenetically-engineeredenzymedeliveredbyaviralvectorthatstimulatesCocH productionintheliver,metabolizingcocainebeforeitreachesthebrain.Inratsandmonkeysourpreliminary datashowthatCocHreducesorstopscocaineseeking,anditseffectsformonthstoyears(Ankeretal.2012; Gengetal.2013;Zlebniketal.2013).Similarmethodsmaybeavailableforotherdrugsofabuse. Theoverallstrategyusedinthisproposalistoexaminethe3treatmentsindividuallyandin combinationsof2or3inmaleandfemalemonkeysandinthefollicularandlutealphaseofthemenstrualcycle. Cocaineself-administrationwillbecomparedtoalcoholonbehavioralmeasuresofimpulsivedrugchoicebya delay-discountingschedulethatoffersasmallamountofdrugimmediatelyoralargeramountafteradelayand compulsivedrug-seekingthatoccursduringdailyextendedaccessandisdetectedbyelevatedbreak-pointson aprogressive-ratioschedule.Thesebehavioraltaskswillbeassessedwithcocaineandalcohol,andtreatments willbeadministeredundereachcondition.Doseresponsefunctionshavebeenpreviouslystudied,andan optimalconcentrationswillbechosen.First,drugintakewillbereducedbythenondrugreward,SACC.The secondtreatmentwillbePRO,followedbyaSACC+PROcombination,andthethirdtreatmentwillbeCocH alone,thencombinedwithSACCandPRO;SACC+PRO+CocH.Eachtreatmentandcombinationwillbe followedbyano-treatmentwashoutperiod.Itishypothesizedthatadditivetreatmentswillbemoreeffective thansingletreatments.SincetheCocHtreatmentisdependentontheamountofcocaineintheblood,itis hypothesizedthatCocHtreatmentwillbemoreeffectivewhencocainelevelsarelowest,andoncedrug-seekingbehaviorissuppressedbySACCandPRO,itwillremainlowwhenthesetreatmentsareremoved.Itis alsohypothesizedthatfemaleswillbemoreresponsivetotreatmentthanmalesundertheSACC,PROand combinationconditions,butsexdifferenceshavenotbeenfoundfortheCocHcondition.